KR20080112270A - Compositions and methods for the treatment of immunoinflammatory disorders - Google Patents

Abstract

The invention features methods and kits for treating an immunoinflammatory disorder, by administering to a patient diagnosed with or at risk of developing such immunoinflammatory disorder an adenosine activity upregulator in combination with one or more additional agents. ® KIPO & WIPO 2009

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF IMMUNOINFLAMMATORY DISORDERS}

The present invention relates to the treatment of immunoinflammatory diseases.

Immunoinflammatory disorders are characterized by inappropriate activation of the body's immune defenses. The immune response targets and damages tissues of the body itself or transplanted tissues, instead of targeting an infectious invader. The tissue targeted by the immune system depends on the disease. For example, the immune response targets the digestive tract in Crohn's disease, whereas in multiple sclerosis, it targets nerve tissue.

Immune inflammatory diseases affect millions of people and include asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatosis, inflammatory bowel or gastrointestinal disorders (eg Crohn's disease and ulcerative colitis). ), Multiple sclerosis, myasthenia gravis, pruritis / inflammation, psoriasis, rheumatoid arthritis, sclerosis, and systemic lupus erythematosus.

Current treatments for immunoinflammatory diseases, transplanted organ rejection and graft versus host disease typically rely on immunosuppressive agents. Steroids are well known powerful immunosuppressants. However, chronic administration of steroids at immunosuppressive doses is limited because of their well-known toxicity, and the effectiveness of these drugs can vary and their use often carries deleterious side effects. For example, long-term use of steroids is associated with osteoporosis, hypertension, nervous system complications, suboptimal immune responses, and ocular disturbances, even if use is limited in therapeutic situations. Thus, there is a need for improved therapies and methods for the treatment of immunoinflammatory disorders.

There is a need for additional agents for the treatment of immunoinflammatory diseases.

[Summary of invention]

The present invention generally provides methods and kits for treating immunoinflammatory disorders by administering adenosine activity upregulators in combination with corticosteroids, or any other other companion compounds, to a patient in need thereof. It features.

In one aspect, the present invention provides a group B adenosine activity upregulator with corticosteroids, NSAIDs, or NsIDIs to treat an immunoinflammatory disease in a patient diagnosed with or at risk of developing an immunoinflammatory disease. A method of treating an immunoinflammatory disorder is characterized by administering simultaneously or in sufficient amounts to each other within 14 days, 10 days, 5 days, 24 hours, or 1 hour.

In addition, third drugs such as corticosteroids, NSAIDs; COX-2 inhibitors; Biological agents; Small molecule immunomodulators; DMARD; Xanthine; NsIDIs, anticholinergic compounds; Beta receptor agonists; Bronchodilators; Vitamin D analogs; Soralene; Retinoids; Or 5-amino salicylic acid is administered to the patient such that the Group B adenosine activity enhancing modulator, the second drug, and the third drug are administered simultaneously or within 14 days, 10 days, 5 days, or 24 hours of each other in an amount sufficient to treat the patient. May be administered.

Moreover, the present invention provides a composition comprising (i) a group B adenosine activity enhancing modulator and a second drug, such as a corticosteroid, NSAID, or NsIDI, and (ii) the composition being diagnosed or at risk of developing an immunoinflammatory disease. And a kit comprising instructions for administration to the patient.

In addition, the present invention relates to (i) a group B adenosine activity enhancing modulator (ii) a second drug such as corticosteroid, NSAID, or NsIDI, and (iii) the group B adenosine activity enhancing modulator and the second drug are immunoinflammatory. And a kit comprising instructions for administration to a patient diagnosed with or at risk of developing the disease.

Moreover, the present invention relates to a subject comprising (i) a drug, such as a corticosteroid, corticosteroid, NSAID, or NsIDI, and (ii) the Group B adenosine activity enhancing modulator and the drug to a patient diagnosed with or at risk of developing an immunoinflammatory disorder. And a kit containing instructions for administration.

In addition, the present invention provides a patient diagnosed with or at risk of developing (i) a Group B adenosine activity enhancing modulator and (ii) a Group B adenosine activity enhancing modulator and a second drug, such as a corticosteroid, NSAID, or NsIDI as an immunoinflammatory disorder. And a kit comprising instructions for administering to the patient.

Combination therapies of the present invention are other anti-cytokine drugs or drugs that affect cell adhesion, ie IL-6, IL-1, IL-2, IL-12, IL Amounts to diseases such as biologics or small molecules that block the activity of -15 or TNFα (e.g., etanercept, adlimumab, infliximab, or CDP-870) It is useful for use in the treatment of immunoinflammatory diseases in combination with drugs that modulate a sexually acting immune response. In this example (drugs that block the effects of TNFα), the combination therapy reduces the production of cytokines, etanercepts or infliximab that act on the rest of the inflammatory cytokine, enhancing the therapeutic effect. Examples of low molecular weight drugs that block cytokines or modulate the immune response include p38 MAP kinase (eg doramapimod, SCIO-469, VX-702), ICE (eg pranacaic acid) and TACE (eg Examples include drugs that inhibit BMS-561392).

Any of the methods, compositions, and kits of the invention, analogs of certain compounds, may be used in place of the compounds described above themselves. Suitable analogs are described herein. Structural analogs of a compound (eg prednisolone) or a group of compounds (eg corticosteroids) do not have to have the same activity as the compound or group to which the compound is related. Thus, SSRI analogs do not necessarily inhibit serotonin reuptake.

Preferably, the methods, compositions, and kits of the present invention suffer from improved efficacy, safety, tolerance, or immunoinflammatory disorders, as compared to methods and compositions that individually use each component of the combination. Satisfaction with treatment of patients at risk of suffering or suffering.

In certain embodiments of any of the methods of the invention, the Group B adenosine activity enhancing modulators and / or partner compounds are simultaneously, or 14 days, 10 days, 5 days, 24 hours, or 1 with each other at the high or low doses disclosed herein. It can be administered within hours. In certain embodiments of any of the methods of the invention, the Group B adenosine activity enhancing modulator and the second drug may be administered together in a single composition or in separate formulations. In the case of the second drug, a corticosteroid, the Group B adenosine activity enhancing modulator is in any effective dose, with an effective corticosteroid dose such as 0.1-1500 mg / day, 0.5-30 mg / day, or 0.5-10 mg / day. May be administered together. The composition can be formulated for topical or systemic administration, for example. Unit dosage forms of such formulations may be oral, topical, parenteral, rectal, skin and / or subcutaneous.

In certain embodiments of the compositions, kits, and methods of the present invention, pharmacologically active agents used in the composition or kit, or method are described. In this embodiment, pharmacologically inactive excipients may also be present in the composition.

In addition, the compounds useful in the present invention may be isotopically labeled compounds. Useful isotopes are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine (eg, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S , ¹⁸ F, and ³⁶ Cl). Isotopically-labeled compounds can be prepared by synthesizing the compounds using readily commercially available isotopically-labeled reagents instead of non-isotopically-labeled reagents.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise indicated in the context, the following terms used herein are intended to have the following meanings in interpreting the present invention.

"A Group A adenosine activity upreguiator" means a compound having Formula (I):

,

, 또는

이다.Wherein each Z and each Z 'is independently N, O, C,

,

, or

to be.

일 경우, p=1이고, Z 또는 Z'가 N,

, 또는

일 경우, p=2이며, Z 또는 Z'가 C일 경우, p=3이다. 화학식 (I)에서, 각각의 R₁은, 독립적으로, X, OH, N-알킬 (여기서 알킬기는 1 내지 20, 더 바람직하게는 1-5의 탄소 원자를 가진다); 1 내지 20, 더 바람직하게는 1-5의 탄소 원자를 갖는 분지되거나 분지되지 않은 알킬기; 또는 본 명세서에 정의된 것과 같은 헤테로고리이다. 그 대신에, p>l일 경우, 보통 Z 또는 Z' 원자로부터 두 개의 R₁ 그룹은, 서로 결합하여, -(CY₂)_k- 로 나타낼 수 있으며, 여기서 k는 4 및 6 사이의 정수이다. 각각의 X는, 독립적으로, Y, CY₃, C(CY₃)₃, CY₂CY₃, (CY₂)_1-5OY, 상기 구조 C_nY_{2n -1}의 치환되거나 치환되지 않은 사이클로알케인, 여기서 n= 3-7이다. 각각의 Y는, 독립적으로, H, F, Cl, Br, 또는 I이다. 하나의 실시예에서, 각각의 Z는 동일한 모이어티(moiety)이고, 각각의 Z'는 동일한 모이어티이며, Z 및 Z'는 다른 모이어티들이다.Z or Z 'is O or

, P = 1 and Z or Z 'is N,

, or

In the case of p = 2, when Z or Z 'is C, p = 3. In formula (I), each R ₁ is, independently, X, OH, N-alkyl, wherein the alkyl group has 1 to 20, more preferably 1-5 carbon atoms; Branched or unbranched alkyl groups having 1 to 20, more preferably 1-5 carbon atoms; Or a heterocycle as defined herein. Instead, when p> l, two R ₁ groups, usually from the Z or Z 'atom, may be bonded to each other and represented by-(CY ₂ ) _k- , where k is an integer between 4 and 6 . Each X is, independently, Y, CY ₃ , C (CY ₃ ) ₃ , CY ₂ CY ₃ , (CY ₂ ) _1-5 OY, substituted or unsubstituted cycloal of the structure C _n Y _{2n -1} Kane, where n = 3-7. Each Y is independently H, F, Cl, Br, or I. In one embodiment, each Z is the same moiety, each Z 'is the same moiety, and Z and Z' are other moieties.

Examples of group A adenosine activity enhancing modulators are dipyridamole (also known as 2,6-bis (diethanolamino) -4,8-dipiperidinopyrimido (5,4-d) pyrimidine); 2,6-unsubstituted 4,8-dibenzylaminopyrimido [5,4-d] pyrimidines; Fur mallet; Dipyridamole monoacetate; 2,6-di- (2,2-dimethyl-l, 3-dioxolan-4-yl) -methoxy-4,8-di-piperidinopyrimidopyrimidine; 2,6-bis- (2,3-dimethyoxypropoxy) -4,8-di-piperidinopyrimidopyrimidines; 2,6-bis [N, N-di (2-methoxy) ethyl] -4,6-di-piperidinopyrimidopyrimidine, and 2,6-bis (diethanolamino) -4,8 -Di-4-methoxybenzylaminopyrimidopyrimidine. Other tetra-substituted pyrimidopyrimidines are disclosed in US Pat. Nos. 3,031,450 and 4,963,541, each of which is incorporated herein by reference.

By “a Group B adenosine activity upregulator” is meant any compound that is not a Group A adenosine activity enhancer while mimicking or enhancing the physiological effects of adenosine and adenosine. Examples of group B adenosine activity enhancing modulators include adenosine, as well as certain adenosine receptor agonists, adenosine transport inhibitors, adenosine kinase inhibitors, adenylate cyclase inhibitors, adenosine deminase inhibitors, calmodin antagonists, and Phosphodiesterase inhibitors.

By “an amount sufficient” is meant, in the combination of the present invention, the amount of compound required to treat or prevent a musculoskeletal disorder or an immunoinflammatory disorder (or pain associated therewith) in a clinically relevant method. The sufficient amount of active compound used in the practice of the present invention for the treatment of abnormalities caused by or due to an immunoinflammatory disease depends on the mode of administration, the age, weight, and general health of the patient. Eventually, the prescriber will determine the appropriate amount and dose regimen. In addition, the term “an effective amount” refers to the use of each drug measured and approved by regulatory authorities (such as the US Food and Drug Administration) alone in the treatment of patients with musculoskeletal or immunoinflammatory disorders. By the safe and efficacious combination therapy of the invention is meant the amount of the compound.

"Anticonvulsant" means a drug used for the prevention of epileptic seizures. Examples of anticonvulsants include carbanazepine, oxcarbazepine, lamotrigine, phenytoin, topiramate, levetivacetam, gavapentin, And valproic acid.

By "corticosteroid" is meant a natural or synthetic compound characterized by a hydrogenated cyclopentanoperhydrophenanthrene ring system. Natural corticosteroids are generally produced by the adrenal cortex. Synthetic corticosteroids can be halogenated. Examples of corticosteroids are provided herein.

Corticosteroids used in the methods, compositions and kits of the invention include, for example, algestone, 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone -methylprednisolone), 6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salt (6-alpha-methylprednisolone 21-hemisuccinate sodium salt) 6-alpha, 9-alpha-difluoroprednisolone 21-acetate 17-butyrate (6-alpha, 9-alpha-difluoroprednisolone 21-acetate 17-butyrate), amcinafal, beclomethasone , Beclomethasone dipropionate, beclomethasone dipropionate monohydrate, 6-beta-hydroxycortisol, betamethasone, Betamethasone Betamethasone-17-valerate, budesonide, clobetasol, clobetasol propionate, clobetasone, clocortolone, clo Cortolone pivalate, cortisone, cortisone, cortisone acetate, cortodoxone, deflazacort, 21-deoxycortisol, deprodone ), Discinolone, desonide, deoxymethasone, dexamethasone, dexamethasone-21-acetate, dichlorisone, dichlorisone Diflorasone, diflorasone diacetate, diflucortolone, doxibetasol, fludrocortisone, flumethasone, flumethasone, flumethasone pivalate (flumethasone piva late, flumoxonide, flunisolide, fluocinonide, fluocinolone acetonide, 9-fluorocortisone, fluorohydroxyandro Fluorohydroxyandrostenedione, fluorometholone, fluorometholone acetate, fluoxymesterone, flupredidene, fluprednisolone, fluandrenoleide (flurandrenolide), formocortal, halcinonide, halomethasone, halomethasone, halopredone, hyrcanoside, hydrocortisone, hydrocortisone acetate (hydrocortisone acetate), hydrocortisone butyrate, hydrocortisone cypionate, hydro Hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone probutate, hydrocortisone valerate, 6-hydroxydexamethasone, 6-hydroxydexamethasone, Isoflupredone, isoflupredone acetate, isoprendinidine, isoprendnidene, meclorisone, methylprednisolone, methylprednisolone acetate, methylprednisolone acetate succinate Methylate (methylprednisolone sodium succinate), paramethasone, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone metasulphobenzoate, prednisolone Prednisolone sodium phosphate, prednisolone tebutate, prednisolone-21-hemisuccinate free acid, prednisolone-21-acetate, prednisolone -21 (beta-D-glucuronide) (prednisolone-21 (beta-D-glucuronide)), prednisone, prednylidene, prodnylidene, procinonide, tralonide Triamcinolone, triamcinolone acetonide, triamcinolone acetonide 21-palmitate, triamcinolone diacetate, triamcinolone, hexacetonone hexacetonine wortmannin). Particularly preferred corticosteroids are prednisolone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, fluticasone, prednisone, triamcinolone and diflurasone. Preferably, the methods, compositions, and kits of the present invention may have improved efficacy, safety, tolerance, or musculoskeletal disorders or as compared to methods and compositions that use each component of the combination separately. Satisfaction with treatment of patients suffering from or at risk of suffering related pain.

"High dosage" means at least 5% (eg, at least 10%, 20%, 30%, 40%, 50) of the highest standard recommended dose of an individual compound for treating any human disease or condition. %, 60%, 70%, 80%, 90%, 100%, 200%, or 300%).

“Low dosage” means at least 5% (eg, at least 10%, 20%, or less) than the lowest standard recommended dose of an individual compound formulated according to a given route of administration for the treatment of any human disease or condition. 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%). For example, low doses of corticosteroids formulated for inhalation will differ from low doses of corticosteroids formulated for oral administration.

By "moderate dosage" is meant a dose between low and high doses.

"More effective" means that a method, composition, or kit is superior to other methods, compositions, or kits compared, is less toxic, safer, more convenient, and more patient tolerable. Or, inexpensive, or providing greater treatment satisfaction. Efficacy can be measured by a practitioner using any standard method appropriate for a given indication.

The term "immunoinflammatory disorder" encompasses a variety of abnormalities, including autoimmune diseases, proliferative skin diseases and inflammatory skin diseases. Immunoinflammatory diseases lead to the destruction of healthy tissue by inflammatory progression, dysregulation of the immune system and unnecessary cell proliferation. Examples of immunoinflammatory disorders include vulgar acne; Acute respiratory distress syndrome; Addison's disease; Allergic rhinitis; Allergic intraocular inflammation, ANCA-associated small-vessel vasculitis; Ankylosing spondylitis; Arthritis, asthma; Atherosclerosis; Atopic dermatitis; Autoimmune hemolytic anemia; Autoimmune hepatitis; Becet's disease; Bell's palsy; Bullous whey; Cerebral ischaemia; Chronic obstructive pulmonary disease; Hardening; Cogan's syndrome; Allergic contact dermatitis; Chronic obstructive pulmonary disease (COPD); Crohn's disease; Cushing's syndrome; Dermatitis; diabetes; Discoid lupus erythematosus; Eosinophilic fasciitis; Nodule erythema; Deciduous dermatitis; Fibromyalgia; Focal glomerulosclerosis; Giant cell arteritis; ventilation; Gouty arthritis; Graft-versus-host disease; Hand eczema; Henoch-Schonlein purpura; Herpes zoster; Hirsutism; Idiopathic cerato-scleritis; Idiopathic pulmonary fibrosis; Idiopathic thrombocytopenic plaque; Immunoinflammatory bowel or gastrointestinal diseases, inflammatory skin diseases; Lichen planus; Lupus nephritis; Lymphoma bronchitis; Macular edema; Multiple sclerosis; Myasthenia gravis; Myositis; Osteoarthritis; Pancreatitis; Pseudomolar pregnancy; Plain cloth spear; Nodular polyarteritis; Rheumatic polymyalgia; Scrotum itching; Pruritis / inflammation, psoriasis; Psoriatic arthritis; Rheumatoid arthritis; Recurrent polyneuropathy; Rosacea caused by sarcoidosis; Rosacea caused by scleroderma; Rosacea caused by Sweet Syndrome; Rosacea caused by systemic lupus erythematosus; Rosacea caused by urticaria; Rosacea caused by shingles-related pain; Sarcoidosis; Scleroderma; Segmental glomerulosclerosis; Septic shock syndrome; Shoulder tendinitis or bursitis; Sjogren's syndrome; Still's disease; Stroke-induced brain cell death; Sweet disease; Systemic lupus erythematosus; Systemic sclerosis; Takayasu's arteritis; Temporal arteritis; Use of toxic epidermal mass; Tuberculosis; Type 1 diabetes; Ulcerative colitis; Uveitis; Vasculitis; And Wegener's granulomatosis. "Non-dermal inflammatory disorders" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma and chronic obstructive pulmonary disease.

"Dermal inflammatory disorders" or "inflammatory dermatoses" include, for example, psoriasis, acute febrile neutropenia, eczema (e.g., dry eczema, sweating eczema, bullous) Hand, plantar eczema), localized plasma cell blepharitis, scleroderma, Behcet's disease, central centripetal lupus erythema, persistent pigmentation erythema, polymorphic erythema, ring granulomas, glossy thyroid, squamous thyroid, percutaneous atrophic thyroid, chronic simple thymus, polar state Molecular dermatitis, necrosis, sarcoidosis, necrosis, urticaria, and transient visible cell dissociation dermatosis.

"Non-dermal inflammatory disorders" include, for example, rheumatoid arthritis, inflammatory bowel disease, asthma and chronic obstructive pulmonary disease.

By "proliferative skin disease" is meant a benign or malignant disease characterized by accelerated cell division in the epidermis or dermis. Examples of proliferative dermatosis include psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, skin and squamous cell carcinoma of the skin, flaky gonads, epidermal exfoliation, malignant bulb keratosis, acne and seborrheic dermatitis to be.

By "musculoskeletal disorder" is meant an immune system-related disorder of muscles, ligaments, bones, joints, cartilage, or other connective tissue. The most commonly occurring musculoskeletal disorders are various forms of arthritis, such as osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and gout. Other musculoskeletal disorders include acquired hyperostosis syndrome, acromegaly, ankylosing spondylitis, Behcet's disease, bone diseases, bursitis, cartilage diseases, chronic fatigue syndrome, compartment Compartment syndromes, congenital hypothyroidism, congenital myopathies, dentigerous cysts, dermatitis, diffuse idiopathic skeletal hyperostosis (Dupuytren's contracture), eosinophilic myalgia syndrome, fasciitis, Felty's syndrome, fibromyalgia, halux valgus, infectious arthritis, joint disease, kabuki syndrome (Kabuki make-up syndrome), Legg-Perthes disease, Lupus, Lyme disease, Melas syndrome, metabolic bone disease , Mitochondrial myopathies, mixed connective tissue diseases, muscle diseases, muscular dystrophies, musculoskeletal abnormalities, musculoskeletal disorders, myositis, osteomyositis, necrotizing fasciitis Pathology, osteogenic deformans, osteochondritis, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, Paget's disease, Pierre Robin syndrome, rheumatoid Polymyalgia, polymyositis, postpoliomyelitis syndrome, pseudogout, psoriatric arthritis, reactive arthritis, Reiter disease, relapsing polychondritis, renal bone Renal osteodystrophy, rhabdomyolysis, rheumatic diseases, rheumatic fe ver, scleroderma, Sever's disease, calceneal apophysitis, Sjogren's syndrome, spinal diseases, spinal stenosis, Still's disease, synoviitis , Jaw joint diseases, tendinopathy, tenis elbow, tendon lubricitis, Tietze's syndrome, and Wegener's granulomatosis.

As will be appreciated by one of ordinary skill in the art to which this invention pertains, an individual disease, disorder, or condition may be characterized as being both musculoskeletal and immunoinflammatory diseases. An example of such a disease is osteoarthritis.

"Pain" is used herein in the most Guam sense and includes acute and chronic pain, such as invasive pain, such as body pain and visceral pain; Neuropathic pain such as central production pain and peripheral production pain; And all kinds of pain, including mental pain. The term preferably means invasive pain, including chronic pain, most preferably body pain and visceral pain.

The term "nociceptive pain" is used to include all pains caused by damage to bone tissues such as, without limitation, cutting, bruising, bone fractures, crush injury, burns and the like. This kind of pain is typically aching, sharp or throbbing. Pain receptors for tissue damage (nociceptors) are mostly present in the skin or in internal organs.

The term "somatic pain" is used to refer to pain arising from bones, joints, muscles, skin, or connective tissue. This kind of pain is typically qualitatively tinged or pulsating and very local.

The term "visceral pain" is used herein to refer to pain arising from internal organs such as the gastrointestinal tract and pancreas. Visceral pain includes painful, fairly localized pain caused by organ capsule-associated tumors. Another type of visceral pain, typically due to the closure of the hollow viscus, is characterized by intermittent spasms and less localized pain.

The term "neuropathic pain" is used herein to refer to pain resulting from sensory input of abnormal processes by the peripheral or central nervous system.

"Non-steroidal anti-inflammatory drug" or "NSAID" means a nonsteroidal drug that prevents or reduces infection. NSAIDs are sodium naproxate, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, pyroxhamm, indomethacin, ibuprofen, nabumethone, choline magnesium trisalicylate, sodium salicylate, salicylic salicylate , Phenopropene, flurbiprofen, ketoprofen, meclofenamate sodium, methoxycampa, oxaprozin, sulfindac, tolmethine, and rofecoxib, celecoxib, valdecoxib, or COX-2 inhibitors such as lumiracoxib.

"Non-steroidal immunophilin-dependent immunosuppressant", or "NsIDI," refers to reducing proinflammatory cytokine production or secretion, binding to immunophilin, or proinflammatory reactions. By any nonsteroidal agent that causes down regulation of. NsIDI is a cyclosporine, tacrolimus, as well as other drugs that inhibit the phosphatase activity of calcineurin (peptides, peptide segments, chemically modified peptides, or peptide mimetics). Calcineurin inhibitors such as ascomycin, pimecrolimus. NsIDI also includes rapamycin (sirolimus) and everolimus, which bind to the FK506-binding protein, FKBP-12, to block antigen-induced proliferation and cytokine secretion.

By "opioid" is meant any agent that binds to opioid receptors. Examples of opioids include, but are not necessarily limited to, codeine, hydrocodone, morphine, hydromorphine, methadone and fentanyl.

By "patient" is meant any animal (eg, a human). Other animals that can be treated using the methods, compositions, and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice. , Lizards, snakes, sheep, cattle, fish, and birds.

"Small molecule immunomodulator" refers to a nonsteroidal agent that reduces proinflammatory cytokine production or secretion, causes down regulation of the proinflammatory response, or otherwise modulates the immune system in an immunophilin-independent manner. By sex, non-NsIDI compounds are meant. Typical small molecule immunomodulators include p38 MAP kinase inhibitors such as VX 702 (Vertex Pharmaceuticals), SCIO 469 (Scios), Doramipmod (Boehringer Ingelheim), RO 30201195 (Roche), and SCIO 323 (Scios), DPC 333 ( TACE inhibitors such as Bristol Myers Squibb, ICE inhibitors such as Vertex Pharmaceuticals, and IMPDH inhibitors such as mycophenolate (Roche) and Vertex Pharamceuticals.

"Sustained release" or "controlled release" means that the therapeutically active component has a therapeutically beneficial blood concentration (but less than a toxic concentration) of the component, for example, in the range of about 12 hours to 24 hours. By sustained over a long period of time, it is meant to be released at a slow rate from the formulation, for example to provide a 12 hour or 24 hour dosage form.

"Systemic administration" means administration of all nondermal routes, in particular excluding topical transdermal administration.

By “treating” is meant to administer or prescribe a composition for the treatment or prevention of a musculoskeletal disorder or an immunoinflammatory disorder.

By "tricyclic antidepressant" is meant a compound having a tricyclic ring structure used for the treatment and prevention of depression. Examples of tricyclic antidepressants include amitriptyline, imipramine, desipramine, nortriptyline, and paroxetine.

Compounds useful in the present invention include racemic mixtures and pure isomers of the compounds described herein, as well as isomers, salts, esters, such as diastereomers and enantiomers. All pharmaceutically acceptable forms of the compounds disclosed herein, including solvates and polymorphs thereof, are included.

The term "pharmaceutically acceptable salt" is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, Salts that meet a moderate benefit / risk ratio are shown. Pharmaceutically acceptable salts are well known in the art. The salts are in position (in the period of the final isolation and purification of the compounds of the invention situ ) or separately by appropriate free acid function reaction with an organic acid. Representative acid addition salts are acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorrate, camphorsulfonate, citrate, cyclopentanepropionate , Digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy- Ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate , Oleate, oxalate, palmitate, pamoate, pectinate, persulfate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salt, and the like do. Representative alkali or alkaline earth metal salts are sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic, as well as tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Ammonium, quaternary ammonium, and amine cations, including but not limited to these.

Other features and advantages of the invention will be apparent from the description and claims.

Detailed description of the invention

The present invention features methods, compositions, and kits useful for the treatment of musculoskeletal disorders, immunoinflammatory disorders, and pain. According to the present invention, musculoskeletal disorders, immunoinflammatory disorders, or pain associated therewith may be associated with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or nonsteroidal immunophilin-dependent immunosuppressants (NsIDIs), or any analog thereof. It can be treated by administering an effective amount of an adenosine activity enhancing modulator or analog thereof, in combination with one or more partner compounds, including. Moreover, according to the present invention, the pain comprises corticosteroids, NSAIDs, opioids, tricyclic antidepressants, anticonvulsants, amantadine, tramadol, oxycodone, buproprione, mexyltine, or capsacin, or any analog thereof. Together with one or more partner compounds, it may be treated by administering an effective amount of an adenosine activity enhancing modulator or analog thereof.

In certain embodiments, each component of the combination of the present invention may only affect a particular disease network and may be insufficient or ineffective on its own, but the combination may optionally be one or more without exhibiting toxicity of each component alone. Increase the therapeutic effect. For example, a combination of adenosine activity enhancing modulators and corticosteroids may exhibit markedly reduced toxicity, with increased anti-immune or immunosuppressive effects when compared to the administration of each agent alone.

In various embodiments, the route of administration includes topical, transdermal, and systemic administration (such as intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intradural, intraperitoneal, intraarticular, ocular, or oral). But it is not necessarily limited thereto. As used herein, "systemic administration" refers to all non-dermal routes of administration, in particular excluding local and transdermal routes of administration.

Any of the foregoing therapies may be administered in conjunction with conventional agents useful for the treatment of musculoskeletal disorders, immunoinflammatory disorders, or pain.

The invention is explained in more detail below.

Adenosine and adenosine activity enhancing modulators ( Adenosine and Adenosine Activity Upregulators )

Endogenous purine nucleoside, adenosine, is an extracellular signaling molecule that interacts with a group of extracellular P ₁ G-protein binding receptors (A ₁ , A _2A , A _2B and A ₃ ). Under certain conditions, local tissue concentration of extracellular ADO is increased after release of AMP, which releases adenosine itself and / or releases extracellular metabolism to produce adenosine.

Adenosine receptor agonists, adenosine transport inhibitors, adenosine kinase inhibitors, adenylate cyclase stimulators (eg, ORG 2766 (Organon), and kolporsin dapropate (Nippon Kayaku, Sanofi-Aventis)), adenosine diades Minase inhibitors (eg, National Cancer Institute (USA), Pfizer), calmodulin antagonists (eg, Novartis Consumer Health and bepridil (RETI)), and phosphodiestera Compounds that mimic the physiological effects of adenosine, such as agent (PDE) inhibitors, are described herein.

Adenosine receptor agonists ( Adenosine receptor agonists )

Examples of adenosine receptor agonists that may be used in the methods, compositions, and kits of the invention include adenosine hemisulfate salts, adenosine amine homologue solids, N ^6- (4-amino-3-iodophenyl) methyl-5 ' -N-methylcarboxamidoadenosine (I-AB-MECA); N-((2-methylphenyl) methyl) adenosine (Metrifudil); 2- (1-hexynyl) -N-methyladenosine (HEMADO); N- (1-methyl-2-phenylethyl) adenosine (R-PIA); N ^6- (R-4-hydroxyphenylisopropyl) adenosine (HPIA); N ⁶ -cyclopentyladenosine (CPA); N ⁶ -cyclopentyl-2- (3-phenylaminocarbonyltriazen-1-yl) adenosine (TCPA); N-((1S, trans) -2-hydroxycyclopentyl) adenosine (GR 79236); N ⁶ -cyclohexyladenosine (CHA); 2-chloro-N ⁶ -cyclopentyladenosine (CCPA); N-ethylcarboxamidoadenosine (NECA); 2- (4- (2-carboxyethyl) phenethylamino) -5'-N-ethylcarboxamidoadenosine (CGS 21680); N ^6- (3-iodobenzyl) -5'-N-methylcarboxamidoadenosine (EB-MECA); 2- (cyclohexylmethylidene hydrazino) adenosine (WRC 0470); 2- (4- (2-carboxyethynyl) phenethylamino) -5'-N-ethylcarboxamidoadenosine (CGS 21680); N ^6- (2- (3,5-dimethoxyphenyl) -2- (2-methylphenyl) ethyl) adenosine (DPMA); Hexynyladenosine-5'-N-ethylcarboxamide (HE-NECA); 2-[(2-aminoethyl-aminocarbonylethyl) phenylethylamino] -5'-N-ethyl-carboxamidoadenosine (APEC); 2-chloro-N ^6- (3-iodobenzyl) -5'-N-methylcarboxamidoadenosine (2-Cl-IB-MECA); 2-phenylaminoadenosine (CV 1808); 3'-aminoadenosine-5'-uronamid; CV terrapuetics ^TM small molecule drug tecadenoson (CVT-510); Legadenoson (CVT 3146); And Carissa (CVT 3033); And Aderis Pharmaceuticals ^TM Low molecular weight drug 2- [2- (4-chlorophenyl) ethoxy] adenosine (MRE 0094), 1-deoxy-1- [6-[[(iodophenyl) methyl] amino] -9H-purine-9- General] -N-methyl-(-D-ribofuranuronamid) (CFlOl), cellodenoson (DTI-0009), apadenoson (University of Virginia) and vinodenoson (MRE-0470). Other adenosine receptor agonists include Gao et al, JPET, 298: 209-218 (2001); U.S. Patents 5,278,150, 5,877,180, 6,232,297; Or disclosed in US Patent Application Publication No. 2005/0261236, and PCT Publication No. WO / 9808855, which are incorporated herein by reference.

Adenosine transport inhibitors ( Adenosine transport inhibitors )

Adenosine transport inhibitors that can be used in the methods, compositions, and kits of the invention include 3- [l- (6,7-diethoxy-2-morpholinoquinazolin-4-yl) piperidine-4 -Yl] -1,6-dimethyl-2,4 (1H, 3H) -quinazolindione hydrochloride (KF24345); 6- (4-nitrobenzyl) -thioinosine (NBI) and 6- (2-hydroxy-5-nitrobenzyl) -thioguanosine (NBG); 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quinolinone (cilostazol); (2-amino-4,5-dimethyl-3-thienyl)-[3- (trifluoromethyl) phenyl] methanone (PD 81723); 3,7-dihydro-3-methyl-1- (5-oxohexyl) -7-propyl-1H-purine-2,6-dione (propentophylline); 6-[(4-nitrobenzyl) thio] -9-β-D-ribofuranosylpurine (nitrobenzylthioinosine) (NBMR); 3,4,5-trimethoxy-, (tetrahydro-1H-1,4-diazepine-1,4 (5H) -diyl) di-3,1-propanedinyl benzoic acid, ester (dilazep); Hexobendine; Dipyridamole; And Fredholm, J. Neurochem. 62: 563-573 (1994), Noji et al., J. Pharmacol. Exp. Ther. 300: 200-205 (2002); And Crawley et al .; Neurosci Lett. Adenosine transport inhibitors, disclosed in 36: 169-174 (1983), each of which is incorporated herein by reference.

Adenosine kinase inhibitors ( Adenosine kinase inhibitors )

Adenosine kinase inhibitors can be used as modulators of adenosine activity enhancement in the methods, compositions, and kits of the invention. Adenosine kinase inhibitors are generally described as analogous to nucleosides or nonnucleosides.

Nucleoside Similar adenosine kinase inhibitors ( Nucleoside - like  adenosine kinase inhibitors )

Nucleoside-like adenosine kinase inhibitors that can be used in the methods, compositions, and kits of the invention include 5-iodotubersidine (5IT) and 2-diaryltubersidine analogs; 5'-deoxo-5'-deoxy-5-iodo tubercidine (5'd-5IT); And 5'-deoxo-5'-aminoadenosine (NH ₂ dADO). Other nucleoside-like adenosine kinase inhibitors are described by McGaraughty et al., Current Topics in Medicinal Chemistry 5: 43-58 (2005); Ugarkar, J. Med. Chem. 43: 2883-2893 (2000); Ugarkar et al., J. Med. Chem. 43: 2894-2905 (2000); Kaplan and Coyle, Eur. J. Pharmacol. 1: 1-8 (1998); And Sinclair et al. Br. J. Pharmacol. 5: 1037-1044 (2001), each of which is incorporated herein by reference.

Nonnucleoside Similar adenosine kinase inhibitors ( Nonnucleoside - like  adenosine kinase inhibitors )

Nonnucleoside-like adenosine kinase inhibitors that can be used in the methods, compositions, and kits of the invention include 5-bromopyrrolopyrrolidines; 4-amino-5- (3-bromophenyl) -7- (6-morpholino-pyridin-3-yl) pyrido [2,3-d] pyrimidine (ABT-702). Other nonnucleoside-like AK inhibitors are described in McGaraughty et al., Current Topics in Medicinal Chemistry 5: 43-58 (2005), Gomtsyan and Lee, Current Pharmaceutical Design 10: 1093-1103 (2004); Jarvis et al. J. Pharm. Exp. Ther. 295: 1156-1164 (2000); Kowaluk, et al. J. Pharm. Exp. Ther. 295: 1165-1174 (2000); And German Patent Application DE 10141212 A1, each of which is incorporated herein by reference.

Phosphodiesterases  Inhibitors ( Phosphodiesterase inhibitors )

Several isozymes of phosphodiesterases act as regulatory switches by catalyzing the degradation of cAMP against adenosine-5-monophosphate (5'-AMP). Phosphodiesterase inhibitors can lead to an increase in cAMP concentrations, followed by an increase in anti-inflammatory action.

Type I Phosphodiesterases  Inhibitors ( Type  I phosphodiesterase inhibitors )

Type I PDE inhibitors that can be used in the methods, compositions, and kits of the present invention include (3-alpha, 16-alpha) -evernnameen-14-carboxylic acid ethyl ester (vinpocetin); 1 8-methoxymethyl-3-isobutyl-1- methylxanthine (MIMX); 1-carboxy-2,3,4,4a, 4b, 5,6,6a, 6b, 7,8,8a, 8b, 9,10,10a, 14,16,17,17a, 17b, 18,19, 19a, 19b, 20,21,21a, 21b, 22,23,23a-dotriacontahydro-14-hydroxy-8a, 10a-bis (hydroxymethyl) -14- (3-methoxy-3-oxo Propyl) -1,4,4a, 6,6a, 17b, 19b, 21b-octamethyl beta-D-glucopyranosiduronic acid (Ks-505a); Cis-5,6a, 7,8,9,9a-hexahydro-2- (4- (trifluoromethyl) phenylmethyl) -5-methyl-cyclopent (4,5) imidazo (2,1- b) Purin-4 (3H) -one (SCH 51866); And 2-o-propoxyphenyl-8-azapurin-6-one (japrinast). Other Type I PDE inhibitors are disclosed in US Patent Application Publication Nos. 2004/0259792 and 2005/0075795, each of which is incorporated herein by reference.

type II Phosphodiesterases  Inhibitors ( Type II phosphodiesterase inhibitors )

Type II PDE inhibitors that can be used in the methods, compositions, and kits of the invention include erythro-9- (2-hydroxy-3-nonyl) adenin (EHNA); 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methyl-2-((2,4,6-trimethylphenyl) imino) -4H-pyrimido (6,1-a) Isoquinolin-4-one (trequinine); ND7001 (Neuro3D Pharmaceuticals); And BAY 60-7550 (Alexis Biochemicals). Other type II PDE inhibitors are disclosed in US Patent Application Publication No. 2003/0176316, each of which is incorporated herein by reference.

type III Phosphodiesterases  Inhibitors ( Type III phosphodiesterase  inhibitors)

Type III PDE inhibitors that can be used in the methods, compositions, and kits of the invention include 3-isobutyl-1-methylxanthine (IBMX); 6-dihydro-2-methyl-6-oxo-3,4'-bipyridine) -5-carbonitrile (milnonone) and N-cyclohexyl-4-((1,2-dihydro-2-oxo -6-quinolinyl) oxy) -N-methyl-butanamid (cilostamide). Other Type III PDE inhibitors are disclosed in the following patents and patent applications, each of which is incorporated herein by reference: EP 0 653 426, EP 0 294 647, EP 0 357 788, EP 0 220 044, EP 0 326 307, EP 0 207 500, EP 0 406 958, EP 0 150 937, EP 0 075 463, EP 0 272 914, and EP 0 112 987, US Pat. No. 4,963,561; 5,141,931, 6,897,229, and 6,156,753; US Patent Application Publication Nos. 2003/0158133, 2004/0097593, 2006/0030611, and 2006/0025463; WO 96/15117; DE 2825048; DE 2727481; DE 2847621; DE 3044568; DE 2837161; And DE 3021792.

type IV Phosphodiesterases  Inhibitors ( Type IV phosphodiesterase inhibitors )

Type IV PDE inhibitors that can be used in the methods, compositions, and kits of the invention include 4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidone (rollipram) and 4- (3-butoxy-4-methoxybenzyl) -2-imidazolidinone (Ro20-1724), scylilolast (GlaxoSmithKline), Slipping (Schering AG), MN 001 (Kyorin Pharmaceutical), arophylline ( Almirall-Prodesfarma, Toffeillast (Pfizer), Oglemilast (Glenmark Pharmaceuticals Ltd), Tetomilast (Otsuka Pharmaceutical), and Roflumilast (ALTANA Pharma). Other Type IV PDE inhibitors are disclosed in the following patents, patent applications and documents, each of which is incorporated herein by reference: US Pat. Nos. 3,892,777, 4,193,926, 4,655,074, 4,965,271, 5,096,906 5,124,455, 5,272,153, 6,569,890, 6,953,853, 6,933,296, 6,919,353, 6,953,810, 6,949,573, 6,909,002, and 6,740,655; United States Patent Application Publication Nos. 2003/0187052, 2003/0187257, 2003/0144300, 2003/0130254, 2003/0186974, 2003/0220352, 2003/0134876, 2004/0048903 2004/0023945, 2004/0044036, 2004/0106641, 2004/0097593, 2004/0242643, 2004/0192701, 2004/0224971, 2004/0220183, 2004/0180900, 2004/0171798, 2004/0167199, 2004/0146561, 2004/0152754, 2004/0229918, 2005/0192336, 2005/0267196, 2005 / 0049258, 2006/0014782, 2006/0004003, 2006/0019932, 2005/0267196, 2005/0222207, 2005/0222207, 2006/0009481; PCT Publication No. WO 92/079778; And Molnar-Kimber, K.L. et al. J. Immunol, 150: 295A (1993).

Type V Phosphodiesterases  Inhibitors ( Type  V phosphodiesterase inhibitors )

Type V PDE inhibitors that can be used in the methods, compositions, and kits of the present invention are described in US Pat. Nos. 6,992,192, 6,984,641, 6,960,587, 6,943,166, 6,878,711, and 6,869,950, and the United States. Patent Application Publication Nos. 2003/0144296, 2003/0171384, 2004/0029891, 2004/0038996, 2004/0186046, 2004/0259792, 2004/0087561, 2005/0054660 , 2005/0042177, 2005/0245544, and 2006/0009481, each of which is incorporated herein by reference.

type VI Phosphodiesterases  Inhibitors ( Type VI phosphodiesterase  inhibitors)

Type VI PDE inhibitors that can be used in the methods, compositions, and kits of the present invention are described in US Patent Application Publication Nos. 2004/0259792, 2004/0248957, 2004/0242673, and 2004/0259880. It includes the disclosed materials, each of which is incorporated herein by reference.

type VII Phosphodiesterases  Inhibitors ( Type VII phosphodiesterase inhibitors )

Type VII PDE inhibitors that can be used in the methods, compositions, and kits of the invention include the materials disclosed in the following patents, patent applications, and documents, each of which is incorporated herein by reference: US Patents 6,838,559, 6,753,340, 6,617,357, and 6,852,720; US Patent Application Publication Nos. 2003/0186988, 2003/0162802, 2003/0191167, 2004/0214843, and 2006/0009481; PCT Publication WO 00/68230; And Martinez et al., J. Med. Chem. 43: 683-689, 2000.

Corticosteroids ( Corticosteroids )

Suitable corticosteroids include glucocorticosteroid receptor agonists (SEGRAs), 1 l-alpha, 17-alpha, 21-trihydroxypren-4-ene-3,20-dione; 11-beta, 16-alpha, 17,21-tetrahydroxypresent-4-ene-3,20-dione; 11-beta, 16-alpha, 17,21-tetrahydroxypresent-1,4-diene-3,20-dione; 11-beta, 17-alpha, 21-trihydroxy-6-alpha-methylpresen-4-ene-3,20-dione; 11-dihydrocorticosterone; 11-dioxycortisol; 11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone; 16-methylhydrocortisone; 17,21-dihydroxy-16-alpha-methylpresna-1,4,9 (11) -triene-3,20-dione; 17-alpha-hydroxypresent-4-ene-3,20-dione; 17-alpha-hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta-presence-9 (11) -ene-3,20-dione; 17-hydroxy-4,6,8 (14) -prenatriene-3,20-dione; 17-hydroxypresna-4,9 (11) -diene-3,20-dione; 18-hydroxycorticosterone; 18-hydroxycortisone; 18-oxocortisol; 21-acetoxypregnenolone; 21-dioxy aldosterone; 21-dioxycortisone; 2-dioxyexidone; 2-methylcortisone; 3-dihydroexidone; 4-presene-17-alpha, 20-beta, 21-triol-3,11-dione; 6,17,20-trihydroxypresent-4-en-3-one; 6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salt, 6-beta-hydroxycortisol, 6-alpha 9-alpha-difluoroprednisolone 21-acetate 17-butyrate, 6-hydroxycorticosterone; 6-hydroxydexamemethasone; 6-hydroxyprednisolone; 9-fluorocortisone; Alclomethasone dipropionate; Aldosterone; Alghero; Alphaderm; Amadinone; Amcinolone; Anageston; Androstenedione; Ancortape acetate; Beclomethasone; Beclomethasone propionate; Betamethasone 17-valorate; Betamethasone sodium acetate; Betamethasone sodium phosphate; Betamethasone balerate; Borosterone; Budesonide; Calusosterone; Chlormadinone; Chloroprednisone; Chloroprednisone acetate; cholesterol; Ciclesonide; Clobetasol; Clobetasol propionate; Clobetason; Clocortolone; Clocortolone pivalate; Clogestone; Cloprednol; Corticosterone; Cortisol; Cortisol acetate; Cortisol butyrate; Cortisol cypionate; Cortisol octanoate; Cortisol sodium phosphate; Cortisol sodium succinate; Cortisol valerate; Cortisone; Cortisone acetate; Cortivazol; Cortodoxone; Daturalone; Deplazacort, 21-dioxycortisol, dihydroepiandrosterone; Delmadinone; Deoxycorticosterone; Deprodon; Descinolone; Desonide; Desoximetason; Dexafen; Dexamethasone; Dexamethasone 21-acetate; Dexamethasone acetate; Dexamethasone sodium phosphate; Dichlorisone; Dipulason; Diflorasone diacetate; Diflucortolone; Difluprenate; Dihydroelatericin a; Domofredate; Doxybetasol; Ecdysone; Ecsterone; Emoxolone; Endlison; Enoxonon; Fluazacort; Flusinolone; Fluchloronide; Fludrocortisone; Fludrocortisone acetate; Flugestone; Flumetasone; Flumethasone pivalate; Flumoksonide; Flunisolide; Fluorocinolone; Fluorocinolone acetonide; Fluorinide; Fluorocortin butyl; 9-fluorocortisone; Fluorocortolone; Fluorohydroxyandrostenedione; Fluorometholone; Fluorometholone acetate; Fluoxymesterone; Fluperolone acetate; Flufreddene; Fluprednisolone; Fluandrenolide; Fluticasone; Propionic acid fluticasone; Formmebolone; Formestane; Formocortal; Gestonolone; Glycerinin; Halogeninide; Halobetasol propionate; Halomethasone; Halopredone; Haloprogesterone; Hydrocortamate; Hydrocortioson cypionate; Hydrocortisone; Hydrocortisone 21-butyrate; Hydrocortisone acetonate; Hydrocortisone acetate; Hydrocortisone butyrate; Hydrocortisone butyrate; Hydrocortisone cypionate; Hydrocortisone hemisuccinate; Hydrocortisone probutate; Hydrocortisone sodium phosphate; Hydrocortisone sodium succinate; Hydrocortisone valerate; Hydroxyprogesterone; Inocosterone; Isoflupredone; Isoflupredone acetate; Isopridniden; Loteprednol ethanecarbonate; Mechlorisone; Mecortolone; Medrogestone; Methoxyprogesterone; Medridone; Megestrol; Megestrol acetate; Melengestrol; Meprednisone; Methanedrostenolone; Methylprednisolone; Methylprednisolone acetonate; Methylprednisolone acetate; Methylprednisolone hemisuccinate; Methylprednisolone sodium succinate; Methyltestosterone; Metribolone; Mometasone; Mometasone furoate; Mometasone furoate monohydrate; Nison; Nomegestrol; Norgestomer; Norbinosterone; Oxymesterone; Paramethasone; Paramethasone acetate; Ponasterone; Prednicarbate; Prednisolamate; Prednisolone; Prednisolone 21-diethylaminoacetate; Prednisolone 21-hemisuccinate; Prednisolone acetate; Prednisolone farnesylate; Prednisolone hemisuccinate; Prednisolone-21 (beta-D-glucuronide); Prednisolone metasulfobenzoate; Prednisolone sodium phosphate; Prednisolone steaglate; Prednisolone tebutate; Prednisolone tetrahydrophthalate; Prednisone; Prednisbal; Prednylidene; Pregnenolone; Prosnonide; Tralonide; Progesterone; Promegestone; Lafontisterone; Limexolone; Oxybolone; Lubrosterone; Styzophylline; Thixocortol; Topteron; Triamcinolone; Triamcinolone acetonide; Triamcinolone acetonide 21-palmitate; Triamcinolone bentonide; Triamcinolone diacetate; Triamcinolone hexaacetonide; Trimegesdon; Turkesterone; And witmanin (wortmannin) may include a material selected from the group consisting of.

Standard recommended doses of various steroid / disease combinations are shown in Table 1 below.

Other standard recommended doses for corticosteroids are described, for example, in Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physician's Desk Reference 2003 (57 ^th Ed. Medical Economics Staff et al. , Medical Economics Co., 2002). In one embodiment, the dose of corticosteroid administered is the same dose as the prednisolone dose defined herein. For example, a low dose of corticosteroid can be thought of as the same dose as a low dose of prednisolone. When the combination of the present invention is used for treatment with corticosteroids, the dose of each component can be substantially reduced, which is administered either alone or in combination with corticosteroids and adenosine activity enhancers. Thereby apparently lower than the dose required to achieve the same effect. For example, in adenosine activity enhancing modulators / corticosteroid combinations, the reduced dose of adenosine activity enhancing modulators or corticosteroids is musculoskeletal disorders and / or immunoinflammatory disorders as compared to a dose suitable for administering each compound alone. Or in the treatment of pain associated therewith. Two or more corticosteroids may be administered in the same treatment.

Steroid receptor modulators ( Steroid Receptor Modulators )

Steroid receptor modulators (eg, antagonists and agonists) can be used in addition to or in addition to corticosteroids in the methods, compositions, and kits of the invention. Thus, in one embodiment, the invention features a combination of adenosine activity enhancing modulators and glucocorticoid receptor modulators or other steroid receptor modulators and methods of treating musculoskeletal disorders and / or immunoinflammatory disorders or pain associated with such disorders.

Glucocorticoid receptor modulators that can be used in the methods, compositions, and kits of the present invention include US Pat. Nos. 6,380,207, 6,380,223, 6,448,405, 6,506,766, and 6,570,020, US Patent Application Publication No. 2003/0176478 , 2003/0171585, 2003/0120081, 2003/0073703, 2002/015631, 2002/0147336, 2002/0107235, 2002/0103217, and 2001/0041802, And the compounds described in PCT Publication No. WO 00/66522, each of which is incorporated herein by reference. Other steroid receptor modulators that may also be used in the methods, compositions, and kits of the present invention include US Pat. Nos. 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, 5,693,647, 5,693,646, and 5,688,810, 5,688,808, and 5,696,130, each of which is incorporated herein by reference.

Other compounds ( Other Compounds )

Other compounds that may be used in place of or in addition to the corticosteroids of the methods, compositions, and kits of the invention include A-348441 (Karo Bio), Adrenal Cortex Extract (GlaxoSmithKline), Alventis, Amebucort ( Schering AG), Amelomethasone (Taisho), ATSA (Pfizer), Bitolterol (Elan), CBP-2011 (InKine Pharmaceutical), Sevarakcetam (Novartis) CGP-13774 (Kissei), Cyclasonide (Altana) ), Cyclomethasone (Aventis), clobetason butyrate (GlaxoSmithKline), cloprenol (Hoffmann-La Roche), colismycin A (Kirin), kurcurvitacin E (NIH), deplazacort (Aventis) , Deprodone propionate (SSP), dexamethasone acefurate (Schering-Plough), dexamethasone linoleate (GlaxoSmithKline), dexamethasone balerate (Abbott), difluprenate (Pfizer), domofrenate (Hoffmann-La Roche), Aventis, Etifredol Decle Acetate (IVAX), Fluazacort (Vicuron), Flumoxonide (Hoffmann-La Roche), Fluorocordine Butyl (Schering AG), Fluorocortolone Monohydrate (Schering AG), GR-250495X (GlaxoSmithKline), Halo Metavar (Novartis), Halopredon (Dainippon), HYC-141 (Fidia), Icometasone Enbutate (Hovione), Etrosinonide (AstraZeneca), L-6485 (Vicuron), Lipocort (Draxis Health) ), Rosicorton (Aventis), Mechlorison (Schering-Plough), Naflocort (Bristol-Myers Squibb), NCX-1015 (NicOx), NCX-1020 (NicOx), NCX-1022 (NicOx), Nicocortonide (Yamanouchi), NIK-236 (Nikken Chemicals), NS-126 (SSP), Org-2766 (Akzo Nobel), Org-6632 (Akzo Nobel), P16CM, Propylsterone (Schering AG), RGH -1113 (Gedeon Richter), Roplefonide (AstraZeneca), Roplefonide Palmitate (AstraZeneca), RPR-106541 (Aventis), RU-26559 (Aventis), Sch-19457 (Schering-Plough), T25 (Matrix Therapeutics ), TBI-PAB (Sigma-Tau), T Beson propionate (Hoffmann-La Roche), Tifluadom (Solvay), Timoffesson (Hoffmann-La Roche), TSC-5 (Takeda), RU24858, RU40066, AL-438, ZK216348, NCX-1004, A276575, And ZK-73634 (Schering AG).

Non-steroidal anti-inflammatory drugs ( Non - steroidal Anti - inflammatory Drugs )

Preferably, the adenosine activity enhancing modulator is, for example, acetoaminophen, sodium naproxate, diclofenac sodium, diclofenac potassium, aspirin, sullindac, diflunisal, pyricampam, indomethacin, ibuprofen, nabumethone, choline magnesium tri Salicylate, sodium salicylate, salicylic salicylic acid (salsalate), phenopropene, flubiprofen, ketoprofen, meclofenamate sodium, methoxycampa, oxaprozin, sullindac, And one or more non-steroidal anti-inflammatory drugs (NSAIDs) such as tolmetin.

Acetylsalicylic acid, also known under the trademark aspirin, is an acetyl analogue of salicylic acid. Aspirin is useful for the relief of headaches and muscle and joint pain. Aspirin is also effective in reducing fever, inflammation, and swelling and thus has been used, for example, in the treatment of rheumatoid arthritis, rheumatic fever, and mild infections. Thus, in one aspect, a combination of adenosine activity enhancing modulator and acetylsalicylic acid (aspirin) or an analog thereof may also be administered to enhance the treatment or prevention of the aforementioned diseases.

NSAIDs can be administered in conjunction with any of the combinations described herein. For example, a patient suffering from musculoskeletal disorders or immunoinflammatory disorders may be initially treated with a combination of adenosine activity modulators / glucocorticoid receptors, and the patient may also be treated with an NSAID, such as acetylsalicylic acid, in combination with the combinations described above. Can be treated.

Doses of acetylsalicylic acid are known to those skilled in the medical arts and generally range from about 70 mg to about 350 mg per day. If a low or high dose of aspirin is required, formulations containing dipyridamole and aspirin may be 0-25 mg, 25-50 mg, 50-70 mg, 70-75 mg, 75-80 mg, 80-85 mg, 85- It may contain 90 mg, 90-95 mg, 95-100 mg, 100-150 mg, 150-160 mg, 160-250 mg, 250-300 mg, 300-350 mg, or 350-1000 mg of aspirin.

Nonsteroidal Immunophylline -Dependent immunosuppressants ( Nonsteroidal Immunophilin - Dependent Immunosuppressants )

In healthy people, the immune system uses cellular effectors, such as B-cells and T-cells, to target infectious microbes and abnormal cell types, leaving normal cells intact. In people with autoimmune diseases or transplanted organs, activated T-cells damage healthy tissues. Calcineurin inhibitors (e.g., cyclosporins, tacrolimus, pimecrolimus) and rapamycin target many types of immunoregulatory cells, including T-cells, to produce immune responses in organ transplantation and autoimmune diseases. Suppress

In one embodiment, NsIDI is cyclosporine and is in an amount between 0.05 mg / Kg / day and 50 mg / Kg / day (eg, orally between 0.1 mg / Kg / day and 12 mg / Kg / day) Administered. In another embodiment, NsIDI is tacrolimus and is administered in an amount between 0.0001-20 mg / Kg / day (eg, orally between 0.01-0.2 mg / Kg / day). In another embodiment, the NsIDI is rapamycin and is administered in an amount between 0.1-502 mg / day (eg, a single loading dose of 6 mg / day followed by a 2 mg / day maintenance dose). In another embodiment, the NsIDI is everolimus and is administered at a dose of 0.75-8 mg / day. In still other embodiments, the NsIDI is pimecrolimus and is administered in an amount between 0.1 mg / day and 200 mg / day (e.g., 1% cream / twice daily for treating atopic dermatitis or treatment of psoriasis). NsIDI is a calcineurin-binding peptide administered in an amount and frequency sufficient to treat the patient. Two or more NsIDIs may be administered simultaneously.

Cyclosporine ( Cyclosporines )

Cyclosporins are fungal metabolites that contain a class of cyclic oligopeptides that act as immunosuppressants. Cyclosporin A is a hydrophobic cyclic polypeptide consisting of 11 amino acids. It binds to the intracellular receptor cyclophylline to form a complex. Cyclosporine / cycle pilrin complex is Ca ^{2 +} - inhibits calcineurin binds to a specific protein phosphatase calcineurin-calmodulin-dependent serine-threonine. Calcineurin mediates signaling events that require T-cell activity (reviewed in Schreiber et al., Cell 70: 365-368, 1991). Cyclosporins and their functional and structural analogs inhibit T cell-dependent immune responses by inhibiting antigen-triggered signal transduction. This inhibition reduces the expression of proinflammatory cytokines such as IL-2.

Many other cyclosporins (eg, cyclosporins A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclosporin A is marketed under the NEORAL trademark of Novartis. Cyclosporine A structural and functional analogs include cyclosporines having one or more fluorinated amino acids (eg, disclosed in US Pat. No. 5,227,467); Cyclosporines with modified amino acids (eg, disclosed in US Pat. Nos. 5,122,511 and 4,798,823); And deuterated cyclosporin (described in US Patent Application Publication No. 2002/0132763 A1), such as ISAtx247. Additional cyclosporine analogs are disclosed in US Pat. Nos. 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine analogs include D-Sar (α-SMe) ³ Val ² -DH-Cs (209-825), Allo-Thr-2-Cs, norvaline-2-Cs, D-AIa (3-acetylamino) -8 -Cs, Thr-2-Cs, and D-MeSer-3-Cs, D-Ser (O-CH ₂ CH ₂ -OH) -8-Cs, and D-Ser-8-Cs, but not necessarily these It is not limited to, it is Cruz et al. (Antimicrob. Agents Chemother. 44: 143-149, 2000).

Cyclosporin is very hydrophobic and readily precipitates in the presence of water (eg, in contact with body fluids). Methods of providing cyclosporin formulations with improved bioavailability are disclosed in US Pat. Nos. 4,388,307, 6,468,968, 5,051,402, 5,342,625, 5,977,066, and 6,022,852. Cyclosporine microemulsion compositions are disclosed in US Pat. Nos. 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840, and 6,024,978.

Cyclosporin may be administered intravenously or orally, but oral administration is preferred. To overcome the hydrophobicity of cyclosporin A, intravenous cyclosporin A may be provided in an ethanol-polyoxyethylated castor oil vehicle that must be diluted prior to administration. Cyclosporin A can be provided, for example, as a microemulsion in a 25 mg or 100 mg tablet or as a 100 mg / ml oral solution (NEORAL).

Typically, the patient dose of oral cyclosporin varies with the patient's condition, but some standard recommended doses are described herein. Patients undergoing organ transplants typically receive an initial dose of oral cyclosporin A in amounts between 12 mg / kg / day and 15 mg / kg / day. The dose is then reduced by 5% per week until slowly reaching a 7-12 mg / kg / day maintenance dose. Intravenous administration of 2 to 6 mg / kg / day is preferred for most patients. In patients diagnosed with Crohn's disease or ulcerative colitis, a 6-8 mg / kg / day dose is generally administered. In patients diagnosed with systemic lupus erythematosus, a dose of 2.2 to 6.0 mg / kg / day is generally administered. For psoriasis or rheumatoid arthritis, a dose of 0.5 to 4 mg / kg / day is typical. The proposed dose schedules are shown in Table 2. Other useful doses include 0.5 to 5 mg / kg / day, 5 to 10 mg / kg / day, 10 to 15 mg / kg / day, 15 to 20 mg / kg / day, or 20 to 25 mg / kg / day. Include.

Often cyclosporin is administered in conjunction with other immunosuppressive agents such as glucocorticoids.

Legend

CsA = cyclosporin A

RA = rheumatoid arthritis

UC = ulcerative colitis

SLE = systemic lupus erythematosus

Tacrolimus Tacrolimus )

Tacrolimus (FK506) is an immunosuppressive agent that targets intracellular signaling pathways of T cells. Tacrolimus binds to the intracellular protein FK506 binding protein (FKBP-12), which is structurally unrelated to cyclophilin. The FKBP / FK506 complex binds to calcineurin and inhibits phosphatase activity of calcineurin (Harding et al. Nature 341: 758-7601, 1989; Siekienka et al. Nature 341: 755-757, 1989; and Soltoff et al. J. Biol. Chem. 267: 17472-17477, 1992). This inhibition is dephosphorylation and nuclear potential of the nuclear factor (NFAT) of activated T cells, a nuclear component that initiates gene transcription necessary for proinflammatory cytokines (eg, IL-2, gamma interferon) production and T cell activation. To block. Thus, tacrolimus inhibits T cell activity.

Tacrolimus is Streptomyces Tsukuba N-Sys (Streptomyces tsukubaensis ) is a macrolide antibiotic produced by tsukubaensis . It suppresses the immune system and prolongs the survival of transplanted organs. It is generally available in oral and injection formulations. Tacrolimus capsules contain 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus in a gelatin capsule shell. Injectable formulations include 5 mg anhydrous tacrolimus in castor oil and alcohol diluted with 0.9% sodium chloride or 5% glucose prior to injection. Oral administration is preferred, but injectable tacrolimus is administered to patients who cannot take oral capsules. The initial dose should be administered by continuous intravenous infusion 6 hours after transplantation.

Tacrolimus and tacrolimus analogs are described by Tanaka et al., (J. Am. Chem. Soc., 109: 5031, 1987) and disclosed in US Pat. Nos. 4,894,366, 4,929,611, and 4,956,352. It is. FK506-related compounds including FR-900520, FR-900523, and FR-900525 are disclosed in US Pat. No. 5,254,562; O-aryl, O-alkyl, O-alkenyl, and O-alkynyl macrolides are disclosed in US Pat. Nos. 5,250,678, 532,248, 5,693,648; Amino O-aryl macrolides are disclosed in US Pat. No. 5,262,533; Alkylidene macrolides are disclosed in US Pat. No. 5,284,840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, and N-alkynylheteroaryl macrolides are disclosed in US Pat. No. 5,208,241; Aminomacrolides and derivatives thereof are disclosed in US Pat. No. 5,208,228; Fluoromacrolides are disclosed in US Pat. No. 5,189,042; Amino O-alkyl, O-alkenyl, and O-alkynylmacrolides are disclosed in US Pat. No. 5,162,334; And halo macrolides are disclosed in US Pat. No. 5,143,918.

The proposed dose will vary depending on the condition of the patient, but the standard recommended dose is described below. Typically, patients diagnosed with Crohn's disease or ulcerative colitis are administered 0.1 to 0.2 mg / kg / day oral tacrolimus. Patients transplanted with organs are typically administered 0.1-0.2 mg / kg / day oral tacrolimus. Patients being treated for rheumatoid arthritis typically receive 1-3 mg / day oral tacrolimus. For psoriasis treatment, oral tacrolimus at 0.01 to 0.15 mg / kg / day is administered to the patient. Atopic dermatitis can be treated by applying a cream containing 0.03 to 0.1% tacrolimus twice a day to the affected area. Patients taking oral tacrolimus capsules typically receive their first dose 6 hours after transplant, or 8-12 hours after intravenous tacrolimus infusion is discontinued. Other suggested tacrolimus doses are 0.005 to 0.01 mg / kg / day, 0.01 to 0.03 mg / kg / day, 0.03 to 0.05 mg / kg / day, 0.05 to 0.07 mg / kg / day, 0.07 to 0.10 mg / kg Per day, from 0.10 to 0.25 mg / kg / day, or from 0.25 to 0.5 mg / kg / day.

Tacrolimus is extensively metabolized by the mixed-function oxidase system, in particular the cytochrome P-450 system. The main mechanisms of metabolism are demethylation and hydroxylation. While various tacrolimus metabolites are likely to exhibit immunosuppressive biological activity, 13-dimethyl metabolites are reported to have the same activity as tacrolimus.

Pimecrolimus ( Pimecrolimus )

Pimecrolimus is a 33-epi-chloro derivative of macrolactam ascomycin. Pimecrolimus structure and functional analogues are disclosed in US Pat. No. 6,384,073. Pimecrolimus is particularly useful for the treatment of atopic dermatitis. Pimecrolimus is generally available in 1% cream. The proposed dose schedule of pimecrolimus is shown in Table 2. Individual dose adjustments will vary depending on the condition of the patient, but some standard recommended doses are described below. Oral pimecrolimus may be administered in an amount of 40 to 60 mg / day for the treatment of psoriasis or rheumatoid arthritis. Pimecrolimus may be administered in an amount of 80 to 160 mg / day for the treatment of Crohn's disease or ulcerative colitis. Patients who have undergone organ transplantation may be administered pimecrolimus at 160-240 mg / day. Patients diagnosed with systemic lupus erythematosus can be administered 40-120 mg / day pimecrolimus. Other useful pimecrolimus doses are from 0.5 to 5 mg / day, 5 to 10 mg / day, 10 to 30 mg / day, 40 to 80 mg / day, 80 to 120 mg / day, or even 120 to 200 mg. Include / day

Rapamycin ( Rapamycin )

Rapamycin is a cyclic lactone produced by Streptomyces high-gloss nose kusu (Streptomyces hygroscopicus). Rapamycin is an immunosuppressive agent that inhibits T cell activity and proliferation. Like cyclosporin and tacrolimus, rapamycin complexes with immunophilin FKBP-12, but rapamycin-FKBP-12 complex does not inhibit calcineurin phosphatase activity. The rapamycin immunophilin complex binds to and inhibits the mammalian kinase target (mTOR) of rapamycin. mTOR is a kinase required for cell-cycle progression. Inhibition of mTOR kinase activity blocks T cell activity and proinflammatory cytokine secretion.

Rapamycin structural and functional analogs include mono- and diacylated rapamycin derivatives (US Pat. No. 4,316,885); Rapamycin water soluble prodrugs (US Pat. No. 4,650,803); Carboxylic acid esters (PCT Publication No. WO 92/05179); Carbamate (US Pat. No. 5,118,678); Amide esters (US Pat. No. 5,118,678); Biotin esters (US Pat. No. 5,504,091); Fluorinated esters (US Pat. No. 5,100,883); Acetal (US Pat. No. 5,151,413); Silyl ethers (US Pat. No. 5,120,842); Bicyclic derivatives (US Pat. No. 5,120,725); Rapamycin dimers (US Pat. No. 5,120,727); O-aryl, O-alkyl, 0-alkenyl and 0-alkynyl derivatives (US Pat. No. 5,258,389); And deuterated rapamycin (US Pat. No. 6,503,921). Additional rapamycin analogs are disclosed in US Pat. Nos. 5,202,332 and 5,169,851.

Rapamycin is commercially available for oral administration of liquid and tablet formulations. RAPAMUNE ^™ liquid contains 1 mg / mL rapamycin diluted with water or orange juice prior to administration. Tablets containing 1 or 2 mg of rapamycin are also commercially available. Rapamycin is preferably administered once daily as soon as possible after transplantation. It is quickly absorbed completely after oral administration. Typically, the patient dose of rapamycin will vary with the patient's condition, but some standard recommended doses are given below. The initial loading dose of rapamycin is 6 mg. Subsequent maintenance doses of 0.5-2 mg / day are typical. Instead, a loading dose of 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg may be used with a 1 mg, 3 mg, 5 mg, 7 mg, or 10 mg maintenance dose per day. For patients weighing less than 40 kg, the rapamycin dose is typically adjusted based on body surface area; Typically a 3 mg / m ² / day loading dose and a 1 mg / m ² / day maintenance dose are administered.

Peptide moiety ( Peptide Moieties )

Natural, synthetic or chemically modified peptides, peptide analogs, peptide fragments that impair calcineurin-mediated dephosphorylation and the nuclear potential of NFAT are suitable for use in practicing the present invention. Examples of peptides that act as calcineurin inhibitors by inhibiting NFAT activity and NFAT transcription factors are described, for example, in Aramburu et al., Science 285: 2129-2133, 1999) and Aramburu et al., Mol. Cell 1: 627-637, 1998). As a class of calcineurin inhibitors, these agents are useful in the methods of the invention.

cure( Therapy )

Treatment in accordance with the present invention may be performed alone or in combination with other treatments and may be provided at home, clinics, clinics, outpatient clinics in hospitals, or hospitals. Treatment may optionally begin at the hospital, allowing the doctor to closely monitor the effectiveness of the treatment and take the necessary action, or may begin at an outpatient clinic. The duration of treatment depends on the type of disease or condition being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment. In addition, people at greater risk of developing immunoinflammatory diseases (eg, those suffering from age-related hormone changes) may be treated to inhibit or slow the onset of symptoms.

In certain embodiments of the methods of the invention, the compounds are administered simultaneously or within 14 days of each other, within 10 days of each other, within 5 days of each other, within 24 hours of each other, or within 1 hour of each other in an amount sufficient to treat the patient. The compounds may be formulated together as a single composition, or may be formulated and administered separately. Either or both of these compounds may be administered in low or high doses, each of which is defined herein. Corticosteroids, NSAIDs (e.g., sodium naproxate, diclofenacsodium, diclofenacpotassium, aspirin, sullindac, diflunisal, pyricampam, indomethacin, ibuprofen, nabumethone, magnesium choline, salicylic acid Sodium, salicylic salicylic acid, phenopropene, flurbiprofen, ketoprofen, sodium meclofenamate, meloxycamp, oxaprozin, sulindac, and tolmethine), NsIDIs (e.g., cyclosporine, tarta) It may be desirable to administer compounds such as Crowlimus, Pimecrolimus, and ISAtx247), or analogs thereof. Combination therapies of the present invention are particularly useful for use in the treatment of immunoinflammatory diseases in combination with agents that positively act on the disease and modulate the immune response. Such agents include agents that remove major inflammatory cells, agents that affect cell adhesion, or agents that affect cytokines associated with the immune response. The last category is proinflammatory drugs such as IL-6, IL-1, IL-2, IL-12, IL-15 or TNFα, as well as drugs that mimic or increase the action of anti-inflammatory cytokines such as IL-1O. Agents that inhibit the activity of cytokines. Agents that inhibit TNFα include etanercept, adelimumab, infliximab, or CDP-870. In an embodiment herein (agents that block the effect of TNFα), the combination therapy reduces the production of cytokines, etanercept or infliximab acting on the remainder of the inflammatory cytokine, providing improved treatment. do. Small molecule immunomodulators include, for example, p38 MAP kinase inhibitors such as VX 702, SCIO 469, doramatimod, TACE inhibitors such as RO 30201195, SCIO 323, DPC 333, ICE inhibitors such as pranalcaic acid, and mycophenolate and IMPDH inhibitors such as merimepodive.

In combination therapy, the dose and frequency of administration of each component of the combination can be adjusted independently. For example, one compound may be administered three times a day, unlike other compounds may be administered once a day. Combination therapy may also be performed in an on-and-off cycle, including a rest period that allows the patient's body to recover from any unexpected side effects. In addition, the compounds may be formulated together to deliver all of the compounds in one administration.

The compounds in the study can be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of the compounds is suitably carried out, for example, in the form of physiological saline or by compounds contained in liposomes. If the compound itself is insoluble and not sufficiently dissolved, a solubilizer such as ethanol may be added.

Preferably, the methods, compositions, and kits of the invention are more effective than other methods, compositions, and kits. "More effective" means that the method, composition, or kit is superior to other methods, compositions, or kits compared, is less toxic, safer, more convenient, and better tolerated by the patient, or This means providing cheaper or greater satisfaction with care.

Osteoarthritis Osteoarthritis )

The methods, compositions, and kits of the invention can be used for the treatment of osteoarthritis, or pain associated therewith. If desired, one or more agents typically used in the treatment of osteoarthritis may be used in place of the corticosteroids of the methods, compositions, and kits of the present invention. These agents include NSAIDs (e.g., sodium naproxate, diclofenacsodium, diclofenacpotassium, aspirin, sulindac, diflunisal, pyroxicam, indomethacin, ibuprofen, nabumethone, trisalicylic acid magnesium choline, sodium salicylate, salicylic acid Salicylic acid (salsalate), phenopropene, flurbiprofen, ketoprofen, sodium meclofenamate, meloxycamp, oxaprozin, sullindac, and tolmethine), NsIDIs (e.g., cyclosporine, talc) Crawllimus, pimecrolimus, and ISAtx247), or analogs thereof. Thus, in one embodiment, the invention features methods and kits for the treatment of adenosine activity enhancing modulators with any of the agents described above, osteoarthritis, or pain associated therewith.

Chronic obstructive pulmonary disease ( Chronic Obstructive Pulmonary Disease )

In one embodiment, the methods, compositions, and kits of the invention are used for the treatment of chronic obstructive pulmonary disease (COPD). If desired, one or more agents typically used to treat COPD can be used in the methods, compositions, and kits of the invention in place of or in addition to corticosteroids. Such agents include xanthine (eg, theophylline), anticholinergic compounds (eg, ipratropium, tiotropium), biological agents, small molecule immunomodulators, and beta receptor agonists / bronchodilators (eg, Ibuterol sulfate, bitolterol mesylate, epinephrine, formoterol fumarate, isoproteronol, revalbuterol hydrochloric acid, metaproterenol sulfate, pybuterol acetate, salmeterol xinapoate, and terbutalin) Include. Thus, in one embodiment, the invention features a combination of adenosine activity enhancing modulator and bronchodilator and a method of treating COPD using the same.

psoriasis( Psoriasis )

The methods, compositions, and kits of the invention can be used to treat psoriasis. If desired, one or more psoriasis therapeutics typically used to treat psoriasis may be used in the methods, compositions and kits of the invention in place of or in addition to corticosteroids. Such agents include biological agents (eg, alefacept, infliximab, adalimumab, efalizumab, etanercept, and CDP-870), small molecule immunomodulators (eg, VX 702, SCIO 469, doramati) Mod, RO 30201195, SCIO 323, DPC 333, pranalcaic acid, mycophenolate, and merimepodeep), nonsteroidal immunophilin-dependent immunosuppressants (eg, cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), vitamin D analogues (e.g. calcipotriene, calcipotriol), soralene (e.g. methoxalene), retinoids (e.g. acitretin, tazoreten), DMARDs (e.g. methotrexate ) And anthraline. Therefore, in one embodiment, the present invention features a combination of an adenosine activity enhancing modulator and an antipsoriatic agent and a method of treating psoriasis using the same.

Inflammatory bowel disease ( Inflammatory Bowel Disease )

The methods, compositions, and kits of the invention can be used to treat inflammatory bowel disease. If desired, one or more agents typically used in the treatment of inflammatory bowel disease may be used in the methods, compositions, and kits of the invention in place of or in addition to corticosteroids. Such agents include biological agents (e.g., inflixabab, adelimumab, and CDP-870), small molecule immunomodulators (e.g., VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333 , Pranalcaic acid, mycophenolate, and merimepodeep), nonsteroidal immunophilin-dependent immunosuppressants (eg, cyclosporine, tacrolimus, pimecrolimus, and ISAtx247), 5-amino salicylic acid (eg, Mesalamine, sulfasalazine, balsarazite disodium, and olsalazine sodium), DMARDs (eg, methotrexate and azathioprine) and allosetron. Accordingly, in one embodiment, the invention features a combination of an adenosine activity enhancing modulator with any of the agents described above and a method of treating inflammatory bowel disease using the same.

Rheumatism  arthritis( Rheumatoid Arthritis )

The methods, compositions, and kits of the invention can be used to treat rheumatoid arthritis. If desired, one or more agents typically used in the treatment of rheumatoid arthritis can be used in the methods, compositions, and kits of the invention in place of or in addition to corticosteroids. Such agents include NSAIDs (e.g., sodium naproxate, diclofenacsodium, diclofenacpotassium, aspirin, sulindac, diflunisal, pyroxicam, indomethacin, ibuprofen, nabumethone, magnesium salicylate, sodium salicylate, Salicylic salicylic acid (salsalate), phenopropene, flurbiprofen, ketoprofen, sodium meclofenamate, meloxycamp, oxaprozin, sullindac, and tolmetin), COX-2 inhibitors ( For example, rofecoxib, celecoxib, valdecoxib, and lumiracoxib, biological agents (eg, infliximab, adelimumab, etanercept, CDP-870, rituximab, and atelier Zumab), small molecule immunomodulators (e.g., VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcaic acid, mycophenolate, and merimepodeep), nonsteroidal immunophylline-dependent Immunosuppressive agents (e.g., cyclosporine, tacrolimus, pimecrolyse , And ISAtx247), 5-amino salicylic acid (e.g. mesalamine, sulfasalazine, balsarazite disodium, and olsalazine sodium), DMARDs (e.g. methotrexate, lepronoid, minocycline, oranopine , Gold sodium thiomalate, orothioglucose, and azathioprine), hydroxychloroquine sulfate, and penicillamine. Thus, in one embodiment, the invention features a combination of an adenosine activity enhancing modulator with any of the agents described above and a method of treating rheumatoid arthritis using the same.

asthma( Asthma )

The methods, compositions, and kits of the invention can be used to treat asthma. If desired, one or more agents typically used in the treatment of asthma may be used in the methods, compositions, kits of the invention in place of or in addition to corticosteroids. Such agents include, but are not limited to, beta 2 agonists / bronchodilators / leukotriene modulators (eg, zaphylucaste, montelukast, and xylurton), biological agents (eg, omalizumab), small molecule immunomodulators, anticholinergic compounds, xanthines , Ephedrine, guipennesine, chromoline sodium, nedochromel sodium, and potassium iodide. Thus, in one embodiment, the invention features a combination of an adenosine activity enhancing modulator with any of the agents described above and methods of treating asthma using the same.

ache( Pain )

The methods, compositions, and kits of the invention can be used to treat pain (eg, neuropathic pain or invasive pain). If desired, one or more agents typically used to treat pain can be used in the methods, compositions, and kits of the invention in place of or in addition to corticosteroids. Such agents include NSAIDs, opioids, tricyclic antidepressants, anticonvulsants, amantadine, tramadol, oxycodone, buproprione, mexyltine, and capsaicin. Thus, in one embodiment, the invention features a combination of an adenosine activity enhancing modulator with any of the agents described above and methods of treating pain using the same.

Formulation of the composition ( Formulation of Compositions )

Combinations of the invention can be administered by any suitable means such that proinflammatory cytokine concentrations are inhibited at the target site. The compound can be included in any suitable amount in any suitable carrier material, and is generally present in an amount of 0.1-95% of the total weight of the composition. The composition may be provided in a dosage form suitable for oral, parenteral (eg intravenous, intramuscular), rectal, skin, nasal, vaginal, inhalant, skin (patch), or ocular routes of administration. . Thus, the composition may include, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drinks , Osmotic delivery devices, suppositories, enemas, injections, implants, nebulizers, or nebulizers. The composition may be formulated according to conventional pharmaceutical practice (e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. AR Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York).

Each compound of the pharmaceutical combination may be formulated in a variety of ways well known in the art. For example, the first agent and the second agent may be formulated together or separately. It is preferred that the first agent and the second agent are formulated to administer the agent at the same time or nearly simultaneously.

Agents formulated individually or separately can be packaged together in a kit. The packaging includes, without limitation, for example, a kit comprising two pills, one pill and one powder, one suppository and a liquid in a small bottle, two topical creams, and the like. The kit may include any component that aids in administering a unit dose to a patient, such as a vial for regenerating powder form, a syringe for infusion, a customized IV delivery system, an inhaler, and the like. In addition, unit dose kits may include instructions for preparation and administration of the composition.

Kits may be prepared for single use unit doses for one patient, for multiple use for a particular patient (where certain doses may be needed or individual compounds may vary in efficacy as treatment progresses); Alternatively, the kit may comprise multiple doses suitable for administration to multiple patients (“bulk packaging”). Kit components may be packaged in paper boxes, blister packs, bottles, tubes, and the like.

Solid dosage forms for oral use Solid Dosage Forms for Oral Use )

Oral formulations include tablets containing the active ingredient (s) in a mixture comprising non-toxic pharmaceutically acceptable excipients. Such excipients are, for example, inert diluents or fillers (eg sucrose and sorbitol), lubricants, glidants and non-adhesives (eg magnesium stearate, zinc stearate, Stearic acid, silicas, hydrogenated vegetable oil or talc).

The two compounds may be mixed or dispensed in tablets, capsules or other vehicles. In one embodiment, the first compound is included within the tablet and the second compound is included externally so that most of the second compound may be released prior to release of the first compound.

Formulations for oral use are also hard gelatin capsules in which chewable tablets or active excipients are mixed with inert solid diluents or soft gelatin capsules in which the active excipients are mixed with water or oil vehicles.

Thus, as a composition suitable for oral use, the oral carrier (eg, capsule) may comprise at least 0.01% to 25% (w / w) adenosine activity enhancing modulators or analogs and / or additional agents, preferably 0.01% to 10% active agents between (w / w), more preferably between 0.05% and 4% (w / w). Capsules can be taken from one to four per day or as needed.

Performing the methods described herein is to take the oral vehicle appropriately orally, including adenosine activity enhancing modulators and / or additional agents. For example, the capsule can be taken once in the morning and afternoon by a patient suffering from an immunoinflammatory-related disease such as an immunoinflammatory disease or anti-platelet aggregatory activity.

Topical formulations ( Topical Formulations )

The composition may also be applied for topical use with a topical carrier comprising at least 0.0001% to 25% (w / w) adenosine activity enhancing modulator and at least 0.001% to 25% (w / w) corticosteroid.

In a preferred combination, the corticosteroid and adenosine activity enhancing modulator may be from 0.0001% to 10% (w / w), more preferably from 0.0005% to 4% (w / w) active agent. The cream can be applied once to four times daily or as needed. For example, for prednisolone applied to topical administration, the topical carrier is 0.01 with adenosine activity enhancing modulator between 0.0001% and 2% (w / w), more preferably between 0.0005% and 1% (w / w). It may comprise between% and 5% (w / w), preferably between 0.01% and 2% (w / w), more preferably between 0.01% and 1% (w / w) prednisolone.

In order to carry out the methods described herein, topical carriers comprising adenosine activity upregulators and corticosteroids are applied to the patient's discomfort. For example, cream may be applied to the hand of a patient suffering from arthritic fingers, and topical eye drops may be applied to the eye of the patient to treat uveitis.

inhale( Inhalation )

For intranasal administration or administration by inhalation, the active compounds according to the invention are in the form of solutions or suspensions from pump spray containers squeezed or pumped by the patient or for example dichlorofluoromethane, trichlorofluoromethane It is conveniently transferred in the form of an aerosol spray which is sprayed in a compressed vessel or nebulizer with a suitable propellant such as dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a compressed aerosol, the dosage unit may be defined by a valve for moving the metered amount. The compressed container or nebulizer may comprise a solution or suspension of the active compound. Capsules and cartridges (eg made of gelatin) for use with an inhaler or insufflator may be formulated comprising a mixed powder of the compound according to the invention and a suitable powder such as lactose or starch. have.

Volume( Dosages )

In the enhanced efficacy of the combinations according to the invention, it should be understood that low doses (as defined herein) of tetra-substituted pyrimidopyrimidines or adenosine activity enhancers and / or additional agents may be used. Such doses will vary depending on the health and condition of the patient. Thus intermediate doses or high doses of one or both of the formulations may be used.

In combination, the administration of each drug may be independently one to four times, for example, from one day to one year or even the lifetime of the patient. In many cases chronic long-term administration will be indicated.

The compositions of the present invention are also useful means of elucidating mechanism of action information on biological pathways related to inflammation and novel targets. This information may lead to the development of new combination agents or single agents for the inhibition of proinflammatory cytokine secretion. Methods known in the art to determine biological pathways can be used to determine affected pathways, or networks of pathways, by contacting cells stimulated to produce proinflammatory cytokines with a compound of the present invention. .

These methods can be used to analyze cellular components, positive or negative regulatory compounds and / or novel single agents and combination agents expressed or inhibited after contact with a compound of the present invention as compared to untreated or enzyme activity, nutritional uptake. And methods for analyzing other metabolic activity of the cell, such as proliferation. Cell components analyzed can include gene transcripts and protein expression. Suitable method includes observing the compounds binding to the protein using standard biochemical techniques, the cover (e.g., ¹⁴ C or ³ H labeling), and for example, 2D gels, gene expression profile with a radioactive isotope of a compound of the invention can do. Once identified, such compounds in vivo (in order to prove the tool to add or to develop a new anti-inflammatory drugs in vivo ) model.

Pain and functional indices ( Pain and Function Indices )

In order to measure the efficiency of the methods, compositions and kits according to the invention, a measurement index can be used. Indices useful in the methods, compositions, and kits of the present invention for the measurement of pain associated with musculoskeletal disorders or immunoinflammatory disorders are well known in the art, such as the visual analog scale, Likert scale, and the like. ), The Lequesne index, the WOMAC index and the AUSCAN index. Such indices can be used to measure pain, function, stiffness, or various other things.

Visual Analog Scale (VAS) provides a one-dimensional measurement. VAS is generally used as a representation of distance, such as a line plot drawn with hash marks at average distance intervals, eg, ten 1-cm intervals. For example, a patient may be required to rank the sensations of pain by selecting points on the line that best correspond to the sensations of pain, with "painless" (score of 0 cm) corresponding to one end of the line and being "unbearable." Pain ”(score of 10 cm) corresponds to the other end of the line. This procedure provides a simple and quick approach to obtaining quantitative information about the pain suffered by the patient. VAS scales and their use are described in US Pat. Nos. 6,709,406 and 6,432,937.

Likert scales similarly provide one-dimensional measurements. In general, Likert scales have an integer value between a low value (eg 0 for painless) and a high value (eg 7 for extreme pain). Patients who experience pain are asked to choose a number between a low value and a high value to express the degree of pain experienced. Likert scales and their use are described in US Pat. Nos. 6,623,040 and 6,766,319.

The Lequesne index and Western Ontario and McMaster Universities (WOMAC) osteoarthritis index use a self-administration questionnaire to assess pain, function and stiffness in knee and hip of OA patients. Both knees and hips are covered by WOMAC, and there is one request questionnaire for knees and separated hips. Such questionnaires are useful because they contain more information than VAS or Likert. Both the WOMAC index and the Requestes index are included in surgical settings (eg knee and hip arthroplasty) and are widely effective for OA. Their metric characteristics are not obviously different.

The Australian-Canadian hand arthritis (AUSCAN) index uses identified, reliable and reactive patient self-reported questionnaire. In one embodiment, the questionnaire includes 15 questions within 3 dimensions (pain, 5 questions; intensity, 1 question; and physical function, 9 questions). The AUSCAN index may use, for example, Likert or VAS scale.

In the methods, compositions, and kits of the invention, useful indices for the measurement of pain are the Pain Descriptor Scale (PDS), the Visual Analog Scale (VAS), the Verbal Descriptor Scale (Verbal). Descriptor Scales (VDS), Numeric Pain Intesity Scale (NPIS), Neuropathic Pain Scale (NPS), Neuropathic Pain Symptom Inventory (NPSI), Current Pain List (Present Pain Inventory, PPI), Geriatric Pain Measure (GPM), McGiIl Pain Questionaire (MPQ), Short-Form McGiI Pain Questionaire, Minnesota Facets Minnesota Multiphasic Personality Inventory, Pain Profile and Multidimensional Pain Inventory, Child Heath Questionai re), and Child Assessment Questionaire.

Experiment result( Experimentalal Results )

The effects of test compound combinations on TNFα secretion are shown below in humans stimulated with lipopolysaccharide or phorbol 12-myristate 13-acetate (PMA) and ionomycin. Leukocytes extracted from buffy coat were analyzed. The results of these experiments are shown in FIGS. 1 and 2.

Lipopolysaccharide ( Lipopolysaccharide , LPS )

100 μl suspension of diluted human leukocytes contained within each well of a polystyrene 384-well plate (NalgeNunc) is stimulated to secrete TNFα by treatment of lipopolysaccharide (Sigma L-4130) with a final concentration of 2 μg / mL. When stimulated, various concentrations of each test compound are added. After 16-18 hours of incubation at 37 ° C. in a humidified incubator, the plates were centrifuged to supernatant with white opaque 384-well plates (NalgeNunc, Maxisorb) coated with anti-TNFα antibody (PharMingen, # 551220). Moved. After 2 hours incubation, the plates were washed with PBS containing 0.1% Tween 20 (Tecan Powerwasher 384) and HRP (Pharmingen, combined with biotin-labeled (PharMingen, # 554511) anti-TNFα antibody and streptavidin). # 13047E) and incubated for an additional hour. After washing the plates with 0.1% Tween 20 / PBS, HRP-luminescent material was added to each well and the brightness of each well was measured using an LJL Analyst plate roughness meter.

PMA Ionomycin ( PMA Of ionomycin )

Diluted human leukocytes of 100 μl suspension contained in each well of polystyrene 384-well plate (NalgeNunc) were treated with phorbol 12-myristate 13-acetate (Sigma, P-1585) and 750 with a final concentration of 10 ng / mL. Stimulated to secrete TNFα by treatment with ionomycin (Sigma, I-0634) at ng / mL. When stimulated, various concentrations of each test compound are added. After 16-18 hours of incubation at 37 ° C. in a humidified incubator, the plates were centrifuged to supernatant with white opaque 384-well plates (NalgeNunc, Maxisorb) coated with anti-TNFα antibody (PharMingen, # 551220). Moved. After 2 hours incubation, the plates were washed with PBS containing 0.1% Tween 20 (Tecan Powerwasher 384) and HRP (Pharmingen, combined with biotin-labeled (PharMingen, # 554511) anti-TNFα antibody and streptavidin). # 13047E) and incubated for an additional hour. After washing the plates with 0.1% Tween 20 / PBS, HRP-luminescent material was added to each well and the brightness of each well was measured using an LJL Analyst plate roughness meter.

The synergy score calculated from the combination of compounds described in FIGS. 1 and 2 was calculated by the formula: S = log f _X log f _Y ∑ I _data ( I _data - I _Loewe ), all non-single- Summed for concentration pairs of drugs, the log f _XY represents the natural log of the dilution factor used for each single drug. This effectively calculates the volume between the measured and Loewe additive response surfaces, calibrated against the dilution factor and weighted towards high-low. The synergy scores indicated by the combination of the two agents independently resulted in greater inhibition of TNFα secretion than based on the activity of each of the agents in the combination. The synergy score in the experiment described in FIG. 1 was 2.3. The synergy score in the experimental results illustrated in FIG. 2 was 3.7.

Other embodiments ( Other Embodiments )

Various modifications and variations to the methods and systems described herein without departing from the scope and spirit of the invention will be apparent to those skilled in the art. While the invention has been described in detail with reference to certain preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Furthermore, various modifications of the described methods for carrying out the invention which are obvious to those skilled in medicine, immunology, pharmacology, endocrinology or related fields are intended to fall within the scope of the invention.

All publications mentioned herein are incorporated by reference to the same extent that each independent publication is specifically incorporated by reference herein in its entirety.

1 is a graph depicting the inhibition of LPS-induced TNFα secretion of cells treated with rolipram and prednisolone.

2 is a graph depicting the inhibition of PMA / ionomycin-induced TNFα secretion of cells treated with rolipram and prednisolone.

Claims (19)

Administering to a patient diagnosed with or at risk of developing an immunoinflammatory disorder, a Group B adenosine activity upregulator and a corticosteroid in an amount sufficient to treat the patient simultaneously or within 14 days of each other Method of treating an immunoinflammatory disease comprising the step. The method of claim 1, wherein the method comprises corticosteroids in the patient; Nonsteroidal anti-inflammatory drugs (NSAIDs), nonsteroidal immunophilin-dependent immunosuppressants (NsIDI), COX-2 inhibitors; Biologicals; Small molecule immunomodulators; DMARD; Xanthine; Anticholinergic compounds; Beta receptor agonists; Bronchodilators; Vitamin D analogs (bronchodilators); Psoralens; Retinoids; And administering a third drug selected from the group consisting of 5-amino salicylic acids, wherein said Group B adenosine activity upregulator, said corticosteroid, and said third drug are A method characterized in that it is administered simultaneously or within 14 days of each other in an amount sufficient to treat a patient. The method of claim 1, wherein the immunoinflammatory disease is rheumatoid arthritis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, rheumatoid multiplex Myalgia (polymylagia rheumatica), giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis , Ankylosing spondylitis, cirrhosis, or psoriatic arthritis. The method of claim 1, wherein said Group B adenosine activity enhancing modulator and said corticosteroid are administered within 5 days of each other. 5. The method of claim 4, wherein said Group B adenosine activity upregulator and said corticosteroid are administered within 1 day of each other. 6. The method of claim 5, wherein said Group B adenosine activity upregulator and said corticosteroid are administered within 1 hour of each other. 7. The method of claim 6, wherein said Group B adenosine activity upregulator and said corticosteroid are administered simultaneously. The method of claim 1, wherein the group B adenosine activity enhancing regulators are adenosine (adenosine), adenosine receptor agonist, adenosine transport inhibitor, adenosine kinase inhibitor (adenosine kinase inhibitor), adenylate cycle A method for adenylate cyclase stimulant, adenosine deaminase inhibitor, calmodulin antagonist, or phosphodiesterase inhibitor. According to claim 1, wherein the corticosteroid is algestone (algestone), 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methyl Prednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salt, 6-alpha, 9-alpha- Difluoroprednisolone 21-acetate 17-butyrate (6-alpha, 9-alpha-difluoroprednisolone 21-acetate 17-butyrate), amcinafal, beclomethasone, beclomethasone, beclomethasone dipropionate (beclomethasone dipropionate), beclomethasone dipropionate monohydrate, 6-beta-hydroxycortisol, betamethasone, betamethasone, betamethasone-17-valorate 17-valerate), Budesonide, clobetasol, clobetasol propionate, clobetasone, clocortolone, clocortolone pivalate, cortisone ), Cortisone acetate, cortodoxone, deflazacort, 21-deoxycortisol, deprodone, discinolone, dissonide (desonide), disoximethasone, dexamethasone, dexamethasone, dexamethasone-21-acetate, dichlorisone, diflorasone, diflorasone, diflorason diacetate diflorasone diacetate, diflucortolone, doxibetasol, fludrocortisone, flumethasone, flumethasone pivalate, flumoxonide, flumoxonide, Influenza Fluoride (flunisolide), Fluocinonide, Fluocinolone acetonide, 9-fluorocortisone, Fluorohydroxyandrostenedione, Fluorometholone ( fluorometholone, fluorometholone acetate, fluoxymesterone, flupredidene, fluprednisolone, flurandrenolide, formocortal , Halcinonide, Halometasone, Halometasone, Halopredone, Hyrcanoside, Hydrocortisone, Hydrocortisone acetate, Hydrocortisone butyrate ), Hydrocortisone cypionate, hydrocortisone sodium phosphate isone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone probutate, hydrocortisone valerate, 6-hydroxydexamethasone, isoflupredone (isoflupredone), isoflupredone acetate, isoprednidene, meclorisone, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate sodium succinate, paramethasone, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone acetate, prednisolone metasulphobenzoate, prednisolone sodium phosphate hosphate, prednisolone tebutate, prednisolone-21-hemisuccinate free acid, prednisolone-21-acetate, prednisolone-21 (beta-) D-glucuronide) (prednisolone-21 (beta-D-glucuronide)), prednisone, prednylidene, prodnonide, tralonide, tralonide, triamcinolone Triamcinolone acetonide, triamcinolone acetonide 21-palmitate, triamcinolone diacetate, triamcinolone hexaacetonide, triamcinolone hexacetonin and hexacetonin How to. 10. The method of claim 9, wherein the corticosteroid is prednisolone. The method of claim 1, wherein said Group B adenosine activity upregulator and said corticosteroid are administered in the same pharmaceutical formulation. The method of claim 1, wherein said Group B adenosine activity enhancing modulator or said corticosteroid is formulated for topical administration. The method of claim 1, wherein said Group B adenosine activity enhancing modulator or said corticosteroid is formulated for systemic administration. The method of claim 1, wherein said Group B adenosine activity enhancing modulator or said corticosteroid is administered at a low dose. The method of claim 1, wherein said Group B adenosine activity upregulator or said corticosteroid is administered at a high dose. (i) a composition comprising a Group B adenosine activity enhancing modulator and a corticosteroid, and (ii) a kit comprising instructions for administering the composition to a patient diagnosed with or at risk of developing an immunoinflammatory disorder. (i) group B adenosine activity enhancing modulators, (ii) corticosteroids, and (iii) a kit comprising said group B adenosine activity enhancing modulator and instructions for administering said corticosteroid to a patient diagnosed with or at risk of developing an immunoinflammatory disorder. (i) corticosteroids, and (ii) a kit comprising instructions for administering the corticosteroid and group B adenosine activity enhancing modulator to a patient diagnosed with or at risk of developing an immunoinflammatory disorder. (i) group B adenosine activity enhancing modulators; And (ii) a kit comprising instructions for administering said Group B adenosine activity upregulator and corticosteroids to a patient diagnosed with or at risk of developing an immunoinflammatory disorder.

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